Dibasic non-imidazole histamine H₃ receptor antagonists with a rigid biphenyl scaffold

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• 作者：Giovanni Morini ; Mara Comini ; Mirko Rivara ; Silvia Rivara ; Simone Lorenzi ; Fabrizio Bordi ; Marco Mor ; Lisa Flammini ; Simona Bertoni ; Vigilio Ballabeni et al.
• 关键词：Histamine ; H₃ receptor antagonists ; Non-imidazole ; Biphenyl ; Dibasic
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2006
• 出版时间：1 August 2006
• 年：2006
• 卷：16
• 期：15
• 页码：4063-4067
• 全文大小：219 K

文摘

A class of rigid, dibasic, non-imidazole H₃ antagonists was developed, starting from a series of previously described flexible compounds. The original polymethylene chain between two tertiary amine groups was replaced by a rigid scaffold, composed by a phenyl ring or a biphenyl fragment. Modulation of the distance between the two amine groups, and of their alkyl substituents, was driven by superposition of molecular models and docking into a receptor model, resulting in the identification of 1,1′-[biphenyl-4,4′-diylbis(methylene)]bis-piperidine (5) as a subtype-selective H₃ antagonist with high binding affinity (pK_i = 9.47) at human H₃ histamine receptor.